The present application claims the priority benefit of U.S. provisional application No. 61/871,688, filed Aug. 29, 2013, the entire contents of which are incorporated herein by reference.
The sequence listing that is contained in the file named “MESCP0078US_ST25. txt”, which is 3 KB (as measured in Microsoft Windows®) and was created on Aug. 22, 2014, is filed herewith by electronic submission and is incorporated by reference herein.
1. Field of the Invention
The present invention relates generally to the field of medicine. More particularly, it concerns cyclic peptide inhibitors of lysine-specific demethylase 1 (LSD1).
2. Description of Related Art
Lysine-rich histone tails protrude through nucleosomal DNA strands, and act as sites for several post-translational modifications (PTMs), allowing alteration of higher order chromatin structure. There are numerous lysine methylation sites on histone tails, and PTMs at specific lysine marks can promote transcriptional activation or silencing. The flavin-dependent lysine-specific demethylase 1 (LSD1) selectively removes methyl groups from mono- and di-methylated histone 3 lysine 4 (1-13K4), resulting in gene silencing. More specifically, LSD1 binds to the co-repressor protein CoREST and catalyzes the oxidative demethylation of histone 3 methyllysine 4 (H3K4me1) and histone 3 dimethyllysine 4 (H3K4me2). Methylated histone 3 lysine 4 (H3K4) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by LSD1 is known to aberrantly silence expression of tumor suppressor genes important in human cancer. Because it is overexpressed in many human cancers. LSD 1 has emerged as an important target for the development of specific inhibitors as a new class of antitumor agents.
To date a handful of small molecule inhibitors of LSD1 have been described. Effective LSD1 inhibitors include tranylcypromine-based analogues, such as 1 and 2 (WO2010/084160; WO2011/035941), oligoamines such as verlindamycin (aka 2d) 3 (Huang et al., 2007) and related isosteric ureas and thioureas (Sharma et al., 2010; Sharma et al, 2012), and peptide based LSD1 inhibitors 4 and S (Cuthane et al., 2006; Culhane et al., 2010; Szewczuk et al., 2007; Yang et al., 2007). Fomeris et al. (2007) described a 21 amino acid peptide analogous to the histone 3 lysine tail, wherein Lys4 is replaced by a methionine compound 8, FIG. 1). Although this linear peptide is a potent inhibitor of LSD1/CoREST (Ki 0.04 μM), it has little potential for use as a drug, since it would be poorly transported across membranes, and would be rapidly hydrolyzed in viva. Cyclic peptides are more stable against proteolytic enzymes than their linear counterparts (Hruby et al., 2002), and can facilitate elucidation of bioactive conformations that are important for biological activity. To date, a cyclic peptide inhibitor of LSD1 has not been described.